The overall objective of this project is to investigate the role of Adrenomedullin (ADM) in the lung. ADM is an endogenous peptide which is ubiquitously distributed in human tissues including plasma and it increases during physical exercise. ADM relaxes the smooth muscles of the blood vessels. The vasorelaxant effect is more potent in pulmonary artery than in the aorta. ADM appears to play a role in the regulation of systemic and pulmonary arterial blood pressure. Atrial Natriuretic Peptide (ANP) increases the release of ADM and the hemodynamic effects of ANP may be partially due to ADM. ADM-mRNA is highly expressed in the basal cells of the airway epithelium and Type II pneumocytes in the lung in addition to the cardiovascular tissue, kidney and adrenal medulla. It is possible that ADM is synthesized in the lung tissue and is released into the peripheral blood and airway lumen. An increase in plasma ADM levels has been observed in congestive heart failure and in pulmonary disorders. Yet, the role of ADM in the lung under physiologic and pathophysiologic conditions is not known, in particular the ability of ADM to relax the smooth muscles of the airways. The specific aims are: 1) To study the action and potency of ADM in isolated-perfused lungs where airway responses have been altered by bronchoactive agents. 2) To study the role of airway epithelium, particularly its neutral endopeptidases, on the action of ADM on lung mechanics. 3) To study the role of endothelial derived relaxing factor (EDRF) and cyclooxygenase inhibitors on the action of ADM on lung mechanics. 4) To determine if ADM acts on the airways through cAMP as the second messenger. 5) To determine the site of action of ADM within the airways. The proposed research is significant in that by establishing how ADM regulates bronchodilation it may lead to new therapies in pulmonary diseases characterized by airway obstruction.